The present invention relates to semisynthetic macrolides and compositions which are antibacterial agents, processes for making the compounds, synthetic intermediates employed in the processes, and methods for treatment and prevention of bacterial infections in a mammal.
Erythromycins A through D, represented by formula (E),
are well-known and potent antibacterial agents which are widely used to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which have improved antibacterial activity, less potential for developing resistance, the desired Gram-negative activity, or unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Kashimura, et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published Nov. 11, 1991, and Asaka, et al. have disclosed 5-O-desoaminylerythronolide derivatives 1991, and Asaka, et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
In one embodiment of the present invention are compounds selected from the group consisting of
a compound of formula (I) 
a compound of formula (II) 
xe2x80x83and
a compound of formula (III) 
wherein, in formulas (I)-(III),
Y and Z together are selected from the group consisting of
(1) oxo,
(2) xe2x95x90Nxe2x80x94OH,
(3) xe2x95x90Nxe2x80x94OR1 wherein R1 is selected from the group consisting of
(a) xe2x80x94C1-C12-alkyl,
(b) xe2x80x94C1-C12-alkyl substituted with aryl,
(c) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(d) xe2x80x94C1-C12-alkyl substituted with heteroaryl,
(e) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
(f) xe2x80x94C3xe2x80x94C12-cycloalkyl,
(g) xe2x80x94Si(R2)(R3)(R4), wherein R2, R3, and R4, are each independently xe2x80x94C1-C12xe2x80x94 alkyl or aryl, and
(h) xe2x80x94(CH2)nNR5R6 wherein n is two to six, and R5 and R6 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R5 and R6 taken together with the atom to which they are attached are C3-C12-heterocycloalkyl,
xe2x80x83and
(4) xe2x95x90Nxe2x80x94OC(R7)(R8)(xe2x80x94OR1), wherein R1 is defined above, and R7 and R8 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R7 and R8 taken together with the atom to which they are attached are C3-C12-cycloalkyl, or
one of Y and Z is hydrogen, and the other is selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) xe2x80x94OR1 wherein R1 is defined above, and
(4) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
T is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94, and
(3) xe2x80x94N(W(Rg))xe2x80x94 wherein W is absent or selected from the group consisting of
(a) xe2x80x94Oxe2x80x94,
(b) xe2x80x94(CH2)pxe2x80x94 wherein p is one to six, and
(c) xe2x80x94NHxe2x80x94,
xe2x80x83and
xe2x80x83Rg is selected from the group consisting of
(a) hydrogen,
(b) xe2x80x94C3-C7-cycloalkyl,
(c) aryl,
(d) substituted aryl,
(e) heteroaryl,
(f) substituted heteroaryl,
(g) xe2x80x94C1-C6-alkyl,
(h) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(i) xe2x80x94C1-C6-alkyl substituted with one or more substituents independently selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) xe2x80x94OR1, and
(vii) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
Ra is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 is defined above and q is zero to two,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
Rb is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1 wherein R1 is defined above,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
(6) xe2x80x94C(O)R1 wherein R1 is defined above,
(7) xe2x80x94C(O)OR1 wherein R1 is defined above,
(8) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(9) hydroxyl,
(10) xe2x80x94OR1 wherein R1 is defined above,
(11) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(12) xe2x80x94SO2R1 wherein R1 is defined above;
xe2x80x83and
A, B, D, and E are independently selected from the group consisting of
(1) hydrogen, and
(2) xe2x80x94C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) xe2x80x94Mxe2x80x94R11 wherein M is selected from the group consisting of
(i) a covalent bond,
(ii) xe2x80x94C(O)NHxe2x80x94,
(iii) xe2x80x94NHC(O)xe2x80x94,
(iv) xe2x80x94NHxe2x80x94,
(v) xe2x80x94N(CH3)xe2x80x94,
(vi) xe2x80x94Oxe2x80x94,
(vii) xe2x80x94S(O)nxe2x80x94 wherein n is defined above,
(viii) xe2x80x94C(xe2x95x90NH)NHxe2x80x94,
(ix) xe2x80x94C(O)Oxe2x80x94,
(x) xe2x80x94OC(O)xe2x80x94,
(xi) xe2x80x94OC(O)NHxe2x80x94,
(xii) xe2x80x94NHC(O)Oxe2x80x94, and
(xiii) xe2x80x94NHC(O)NHxe2x80x94,
xe2x80x83and
xe2x80x83R11 is selected from the group consisting of
(i) xe2x80x94C1-C6-alkyl optionally substituted with a substituent selected from the group consisting of
(1xe2x80x2) aryl,
(2xe2x80x2) substituted aryl,
(3xe2x80x2) heteroaryl, and
(4xe2x80x2) substituted heteroaryl,
(ii) aryl,
(iii) substituted aryl,
(iv) heteroaryl,
(v) substituted heteroaryl and
(vi) heterocycloalkyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl,
(f) heterocycloalkyl,
(g) hydroxy,
(h) xe2x80x94C1-C6-alkoxy,
(i) halo, and
(j) xe2x80x94NR15R16 wherein R15 and R16, together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein a moiety selected from the group consisting of
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94NHxe2x80x94,
(iii) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(iv) xe2x80x94N(C1-C6-alkyl substituted with aryl)xe2x80x94,
(v) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(vi) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(vii) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94,
(viii) xe2x80x94Sxe2x80x94, and
(ix) xe2x80x94S(O)qxe2x80x94 wherein q is defined above,
or
any one pair of substituents selected from the group consisting of AB, AD, AE, BD, BE, and DE, taken together with the atom or atoms to which they are attached, are C3-C7-cycloalkyl or a four- to seven-membered ring containing a moiety selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94,
(3) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(4) xe2x80x94N(C1-C6-alkyl substituted with aryl)xe2x80x94,
(5) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(6) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(7) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94, and
(8) xe2x80x94S(O)qxe2x80x94 wherein q is defined above.
In another embodiment of the invention are pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulas (I)-(III) with a pharmaceutically acceptible carrier.
In another embodiment of the invention are methods of treating bacterial infection in a mammal in recognized need of such treatment comprising administering an effective amount of a compound of formulas (I)-(III).
In another embodiment of the invention is disclosed a process for the preparation of a compound of formula (I) 
a compound of formula (II) 
and
a compound of formula (III) 
wherein, in formulas (I)-(III),
Y and Z together are selected from the group consisting of
(1) oxo,
(2) xe2x95x90Nxe2x80x94OH,
(3) xe2x95x90Nxe2x80x94OR1 wherein R1 is selected from the group consisting of
(a) xe2x80x94C1-C12-alkyl,
(b) xe2x80x94C1-C12-alkyl substituted with aryl,
(c) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(d) xe2x80x94C1-C12-alkyl substituted with heteroaryl,
(e) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
(f) xe2x80x94C3-C12-cycloalkyl,
(g) xe2x80x94Si(R2)(R3)(R4), wherein R2, R3, and R4, are each independently xe2x80x94C1-C12-alkyl or aryl, and
(h) xe2x80x94(CH2)nNR5R6 wherein n is two to six, and R5 and R6 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R5 and R6 taken together with the atom to which they are attached are C3-C12-heterocycloalkyl,
xe2x80x83and
(4) xe2x95x90Nxe2x80x94OC(R7)(R8)(xe2x80x94OR1), wherein R1 is defined above, and R7 and R8 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R7 and R8 taken together with the atom to which they are attached are C3-C12-cycloalkyl,
xe2x80x83or
one of Y and Z is hydrogen, and the other is selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) xe2x80x94OR1 wherein R1 is defined above, and
(4) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
T is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94, and
(3) xe2x80x94N(W(Rg))xe2x80x94 wherein W is absent or selected from the group consisting of
(a) xe2x80x94Oxe2x80x94,
(b) xe2x80x94(CH2)pxe2x80x94 wherein p is one to six, and
(c) xe2x80x94NHxe2x80x94,
xe2x80x83and
xe2x80x83Rg is selected from the group consisting of
(a) hydrogen,
(b) xe2x80x94C3-C7-cycloalkyl,
(c) aryl,
(d) substituted aryl,
(e) heteroaryl,
(f) substituted heteroaryl,
(g) xe2x80x94C1-C6-alkyl,
(h) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(i) xe2x80x94C1-C6-alkyl substituted with one or more substituents independently selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) xe2x80x94OR1, and
(vii) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
Ra is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein RI is defined above,
(i) cyano,
(j) xe2x80x94S(O) R1 wherein R1 is defined above and q is zero to two,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
Rb is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1 wherein R1 is defined above,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
(4) xe2x80x94C(O)R1 wherein R1 is defined above,
(5) xe2x80x94C(O)OR1 wherein R1 is defined above,
(6) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(7) hydroxyl,
(8) xe2x80x94OR1 wherein R1 is defined above,
(9) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(10) xe2x80x94SO2R1 wherein R1 is defined above;
xe2x80x83and
A, B, D, and E are independently selected from the group consisting of
(1) hydrogen, and
(2) xe2x80x94C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) xe2x80x94Mxe2x80x94R11 wherein M is selected from the group consisting of
(i) a covalent bond,
(ii) xe2x80x94C(O)NHxe2x80x94,
(iii) xe2x80x94NHC(O)xe2x80x94,
(iv) xe2x80x94NHxe2x80x94,
(v) xe2x80x94N(CH3)xe2x80x94,
(vi) xe2x80x94Oxe2x80x94,
(vii) xe2x80x94S(O)nxe2x80x94 wherein n is defined above,
(viii) xe2x80x94C(xe2x95x90NH)NHxe2x80x94,
(ix) xe2x80x94C(O)Oxe2x80x94,
(x) xe2x80x94OC(O)xe2x80x94,
(xi) xe2x80x94OC(O)NHxe2x80x94,
(xii) xe2x80x94NHC(O)Oxe2x80x94, and
(xiii) xe2x80x94NHC(O)NHxe2x80x94,
xe2x80x83and
xe2x80x83R11 is selected from the group consisting of
(i) xe2x80x94C1-C6-alkyl optionally substituted with a substituent selected from the group consisting of
(1xe2x80x2) aryl,
(2xe2x80x2) substituted aryl,
(3xe2x80x2) heteroaryl, and
(4xe2x80x2) substituted heteroaryl,
(ii) aryl,
(iii) substituted aryl,
(iv) heteroaryl,
(v) substituted heteroaryl and
(vi) heterocycloalkyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl,
(f) heterocycloalkyl,
(g) hydroxy,
(h) xe2x80x94C1-C6-alkoxy,
(i) halo, and
(j) xe2x80x94NR15R16 wherein R15 and R16, together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein a moiety selected from the group consisting of
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94NHxe2x80x94,
(iii) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(iv) xe2x80x94N(C1-C6-alkyl-substituted with aryl)xe2x80x94,
(v) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(vi) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(vii) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94,
(viii) xe2x80x94Sxe2x80x94, and
(ix) xe2x80x94S(O)qxe2x80x94 wherein q is defined above,
xe2x80x83or
any one pair of substituents selected from the group consisting of AB, AD, AE, BD, BE, and DE, taken together with the atom or atoms to which they are attached, are C3-C7-cycloalkyl or a four- to seven-membered ring containing a moiety selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94,
(3) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(4) xe2x80x94N(C1-C6-alkyl substituted with aryl)xe2x80x94,
(5) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(6) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(7) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94, and
(8) xe2x80x94S(O)qxe2x80x94 wherein q is defined above,
the process comprising
(a) reacting a compound of formula (Ia) 
a compound of formula (IIa) 
xe2x80x83or
a compound of formula (IIIa) 
xe2x80x83with an electrophile in the presence of a base, and
(b) optionally deprotecting and isolating the desired product.
In another embodiment of the invention is a process for the preparation of a compound of formula (I) 
a compound of formula (II) 
and
a compound of formula (III) 
wherein, in formulas (I)-(III),
Y and Z together are selected from the group consisting of
(1) oxo,
(2) xe2x95x90Nxe2x80x94OH,
(3) xe2x95x90Nxe2x80x94OR1 wherein R1 is selected from the group consisting of
(a) xe2x80x94C1-C12-alkyl,
(b) xe2x80x94C1-C12-alkyl substituted with aryl,
(c) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(d) xe2x80x94C1-C12-alkyl substituted with heteroaryl,
(e) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
(f) xe2x80x94C3-C12-cycloalkyl,
(g) xe2x80x94Si(R2)(R3)(R4), wherein R2, R3, and R4, are each independently xe2x80x94C1-C12- alkyl or aryl, and
(h) xe2x80x94(CH2)nNR5R6 wherein n is two to six, and R5 and R6 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R5 and R6 taken together with the atom to which they are attached are C3-C12-cycloalkyl,
xe2x80x83and
(4) xe2x95x90Nxe2x80x94OC(R7)(R8)(xe2x80x94OR1), wherein R1 is defined above, and R7 and R8 are independently selected from the group consisting of
(i) hydrogen,
(ii) xe2x80x94C1-C12-alkyl,
(iii) xe2x80x94C1-C12-alkyl substituted with aryl,
(iv) xe2x80x94C1-C12-alkyl substituted with substituted aryl,
(v) xe2x80x94C1-C12-alkyl substituted with heteroaryl, and
(vi) xe2x80x94C1-C12-alkyl substituted with substituted heteroaryl,
xe2x80x83or
xe2x80x83R7 and R8 taken together with the atom to which they are attached are C3-C12-cycloalkyl,
xe2x80x83or
one of Y and Z is hydrogen, and the other is selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) xe2x80x94OR1 wherein R1 is defined above, and
(4) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
T is selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94, and
(3) xe2x80x94N(W(Rg))xe2x80x94 wherein W is absent or selected from the group consisting of
(a) xe2x80x94Oxe2x80x94,
(b) xe2x80x94(CH2)pxe2x80x94 wherein p is one to six, and
(c) xe2x80x94NHxe2x80x94,
xe2x80x83and
xe2x80x83Rg is selected from the group consisting of
(a) hydrogen,
(b) xe2x80x94C3-C7-cycloalkyl,
(c) aryl,
(d) substituted aryl,
(e) heteroaryl,
(f) substituted heteroaryl,
(g) xe2x80x94C1-C6-alkyl,
(h) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(i) xe2x80x94C1-C6-alkyl substituted with one or more substituents independently selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) xe2x80x94OR1, and
(vii) xe2x80x94NR5R6 wherein R5 and R6 are defined above;
Ra is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 is defined above and q is zero to two,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
Rb is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of
(1) xe2x80x94C1-C10-alkyl optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94ORI,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94OR1 wherein R1 is defined above,
(i) cyano,
(j) S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above,
(2) xe2x80x94C3-alkenyl,
(3) xe2x80x94C3-alkynyl,
wherein (2) and (3) can be optionally substituted with a substituent selected from the group consisting of
(a) halogen,
(b) carboxaldehyde,
(c) xe2x80x94CO2R1 wherein R1 is defined above,
(d) xe2x80x94C(O)R1 wherein R1 is defined above,
(e) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(f) cyano,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(4) xe2x80x94C4-C10-alkenyl, and
(5) xe2x80x94C4-C10-alkynyl,
wherein (4) and (5) can be optionally substituted with one or more substituents independently selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) xe2x80x94OR1 wherein R1 is defined above,
(d) oxo,
(e) xe2x80x94NR5R6 wherein R5 and R6 are defined above,
(f) xe2x80x94CO2R1 wherein R1 is defined above,
(g) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(h) xe2x95x90Nxe2x80x94ORI wherein R1 is defined above,
(i) cyano,
(j) xe2x80x94S(O)qR1 wherein R1 and q are defined above,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) heterocycloalkyl,
(p) substituted heterocycloalkyl,
(q) xe2x80x94NHC(O)R1 wherein R1 is defined above,
(r) xe2x80x94NHC(O)NR5R6 wherein R5 and R6 are defined above,
(s) xe2x95x90NNR5R6 wherein R5 and R6 are defined above,
(t) xe2x95x90NNHC(O)R1 wherein R1 is defined above, and
(u) xe2x95x90NNHC(O)NR5R6 wherein R5 and R6 are defined above;
(4) xe2x80x94C(O)R1 wherein R1 is defined above,
(5) xe2x80x94C(O)OR1 wherein R1 is defined above,
(6) xe2x80x94C(O)NR5R6 wherein R5 and R6 are defined above,
(7) hydroxyl,
(8) xe2x80x94OR1 wherein R1 is defined above,
(9) xe2x80x94NR5R6 wherein R5 and R6 are defined above, and
(10) xe2x80x94SO2R1 wherein R1 is defined above;
xe2x80x83and
A, B, D, and E are independently selected from the group consisting of
(1) hydrogen, and
(2) xe2x80x94C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) xe2x80x94Mxe2x80x94R11 wherein M is selected from the group consisting of
(i) a covalent bond,
(ii) xe2x80x94C(O)NHxe2x80x94,
(iii) xe2x80x94NHC(O)xe2x80x94,
(iv) xe2x80x94NHxe2x80x94,
(v) xe2x80x94N(CH3)xe2x80x94,
(vi) xe2x80x94Oxe2x80x94,
(vii) xe2x80x94S(O)nxe2x80x94 wherein n is defined above,
(viii) xe2x80x94C(xe2x95x90NH)NHxe2x80x94,
(ix) xe2x80x94C(O)Oxe2x80x94,
(x) xe2x80x94OC(O)xe2x80x94,
(xi) xe2x80x94OC(O)NHxe2x80x94,
(xii) xe2x80x94NHC(O)Oxe2x80x94, and
(xiii) xe2x80x94NHC(O)NHxe2x80x94,
xe2x80x83and
xe2x80x83R11 is selected from the group consisting of
(i) xe2x80x94C1-C6-alkyl optionally substituted with a substituent selected from the group consisting of
(1xe2x80x2) aryl,
(2xe2x80x2) substituted aryl,
(3xe2x80x2) heteroaryl, and
(4xe2x80x2) substituted heteroaryl,
(ii) aryl,
(iii) substituted aryl,
(iv) heteroaryl,
(v) substituted heteroaryl and
(vi) heterocycloalkyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl,
(f) heterocycloalkyl,
(g) hydroxy,
(h) xe2x80x94C1-C6-alkoxy,
(i) halo, and
(j) xe2x80x94NR15R16 wherein R15 and R16, together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein a moiety selected from the group consisting of
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94NHxe2x80x94,
(iii) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(iv) xe2x80x94N(C1-C6-alkyl-substituted with aryl)xe2x80x94,
(v) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(vi) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(vii) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94,
(viii) xe2x80x94Sxe2x80x94, and
(ix) xe2x80x94S(O)qxe2x80x94 wherein q is defined above,
or
any one pair of substituents selected from the group consisting of AB, AD, AE, BD, BE, and DE, taken together with the atom or atoms to which they are attached, are C3-C7-cycloalkyl or a four- to seven-membered ring containing a moiety selected from the group consisting of
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94NHxe2x80x94,
(3) xe2x80x94N(C1-C6-alkyl)xe2x80x94,
(4) xe2x80x94N(C1-C6-alkyl substituted with aryl)xe2x80x94,
(5) xe2x80x94N(C1-C6-alkyl substituted with substituted aryl)xe2x80x94,
(6) xe2x80x94N(C1-C6-alkyl substituted with heteroaryl)xe2x80x94,
(7) xe2x80x94N(C1-C6-alkyl substituted with substituted heteroaryl)xe2x80x94, and
(8) xe2x80x94S(O)qxe2x80x94 wherein q is defined above,
the process comprising
(a) reacting the compound of formula (Ia) 
a compound of formula (IIa) 
or
a compound of formula (IIIa) 
with an oxidizing agent
and
(b) optionally deprotecting and isolating the desired product.